EP2397167A1 - Device for treating blood outside the body comprising a measurement device for the determination of a luminescence of the spent dialysate - Google Patents

Abstract

Device, comprises: a dialyzer, which is divided into a first and a second chamber (29, 30) by a semipermeable membrane, where the first chamber is arranged in a dialysate path, while the second chamber can be connected to a patient's blood circulation by a blood supply line and a blood discharge line; an inlet (20) for fresh dialysate; an outlet (36) for spent dialysate; and a measuring device (37) including at least one radiation source for monochromatic electromagnetic radiation, and detector system for detecting the intensity of electromagnetic radiation. Device, comprises: a dialyzer, which is divided into a first and a second chamber (29, 30) by a semipermeable membrane, where the first chamber is arranged in a dialysate path, while the second chamber can be connected to a patient's blood circulation by a blood supply line and a blood discharge line; an inlet (20) for fresh dialysate; an outlet (36) for spent dialysate; and a measuring device (37) that is arranged in the outlet and includes at least one radiation source for substantially monochromatic electromagnetic radiation in order to determine a luminescence of the spent dialysate flowing through the outlet, and at least one detector system for detecting the intensity of the electromagnetic radiation generated by luminescence.

Description

The invention relates to a method for the determination of waste products during a dialysis treatment.

In patients with limited or absent renal function, natural metabolic waste products, including uremic toxins, are removed by dialysis, the removal of the substances from the extracorporeal blood by contact of the blood with a dialyzing fluid which is mixed with various salts causes diffusive and convective effects, which are responsible for the transport of material from the blood into the dialysis fluid through a membrane, takes place, the purified blood is then fed back to the patient.

The measure of a patient's dialysis dose can not be based solely on the subjective assessment of the patient's health. It is necessary to quantify the success of dialysis in such a way as to ensure a sufficient dialysis effect. At the same time too high a degree of dialysis due to cost reasons should also be avoided. In order to make the dialysis therapy more efficient, it is necessary to control the dialysis efficiency in real time so as to be able to control the treatment manually or automatically by adjusting the parameters of the dialysis machine.

In order to ensure adequate dialysis therapy, a Kt / N _urea model was developed, whereby urea is one of the waste products in the blood to be purified, which is used to determine an adequate dialysis therapy and where K is the purification power of the dialyzer of urea from the blood in ml / ml. min, t is the treatment time in min and V represents the volume of distribution of urea in ml in the human body, which is directly related to the patient's weight. The dimensionless factor Kt / V _urea defines the reduction of urea nitrogen in the blood when treated three times a week.

Determining the content of urea or toxic substances in the dialysate outflow provides a comprehensive monitoring of the dialysis process, but to this day samples must be taken manually from the system and passed on to a suitably equipped laboratory for chemical analysis.

Therefore, the continuous monitoring of hemodialysis has been demanded (IEEE Engineering in Medicine & Biology Society 11 ^th International Conference), which is caused by the change of conductivity by the hydrolysis of urea and / or other important molecules in the dialysis solution. The calibration of conductivity sensors, which were developed especially for this application, on the other hand, is very laborious, since influences on the conductivity can also arise from other sources. A measuring device that works on this principle is Biostat ^© Urea Monitor from Baxter.

Furthermore, the continuous monitoring of hemodialysis via optical absorbance measurement, which is the transmission of the dialysis fluid, which is essentially influenced by uric acid and other small molecules, can be realized. Such a measuring device is by the UV monitoring system of Fridolin, for example. In EP 1 083 948 B1 described.

However, in addition to the reduction of urea, the removal behavior of other materials, such as medium-sized molecules in the range of 500 to about 50,000 Da, is important in assessing dialysis efficiency, as these are critical for the pathology associated with uremia. These include small proteins and peptides such as β ₂ -microglobulin, cystatin C, retinol-binding protein (RBP) or, for example, complement factor D (VFD). With the devices and methods described above and known from the prior art, it is not possible to continuously monitor the content of these substances during a dialysis treatment in the purified blood or in the outflow of the dialysis fluid. A statement about molecules of medium size, such as β ₂ -microglobulin or other peptides or small proteins, which are largely responsible for the disease course of uremia, but this is not possible.

It is therefore an object of the invention to provide a device with which a statement about the content or the change in the content of medium-sized molecules in the range of 500 to about 50,000 Da can be made in the outflow of the dialysis fluid continuously during the therapy , Thus, a conclusion on the cleaning performance of the therapy with regard to these molecules or the removal rate of these molecules from the blood to be purified would be continuously possible during the therapy in real time.

This object is achieved by a device having the features of claim 1. Advantageous embodiments of the invention can be found in the subclaims.

Absorbance and luminescence measurements are analytical methods for the investigation of molecules in the electromagnetic spectral range. Luminescence measurements are usually used to detect proteins which can be excited via excitable structures, e.g. Fluorophores have been used. In addition to proteins, some peptides and other chemical substances have the ability to emit electromagnetic radiation due to luminescence effects. Such substances also enter the metabolic cycle of mammals in their blood and must be removed therefrom in order to maintain a metabolism that is functional over the long term. When the kidney function of the mammal is impaired; These substances must be removed from the blood of the mammal by renal replacement therapy.

Using the example of fluorescence, special effects of luminescence are exemplified. In the principle of fluorescence measurement, a substance is irradiated with monochromatic electromagnetic radiation of a specific wavelength. If the substance has fluorophores and the incident photons have the molecule-specific energy to excite electrons, the photons are absorbed by changing electrons from a ground state to a higher energetic state. After a typical duration of fluorescence effects of up to about 1μs, the excited electron leaves its higher energetic state and returns to the ground state. It sends the excess energy in the form of photons of a certain wavelength. This wavelength is usually 20-50 nm above the excitation wavelength and is due to energy losses due to non-radiative effects within the energy bands of the molecule. This difference in wavelength is commonly referred to as Stokes shift [" Topics in Fluorescence Spectroscopy, Vol. 1-11, Joseph R. Lakowicz ]. At the same time, however, there are also substances in which the difference between the excitation and emission wavelengths is significantly greater. An example here is p-cresol. The excitation wavelength of this substance is about 300 nm, while the emission wavelength is about 600 nm. Excitation and emission wavelengths are characteristic features of a molecule. Accordingly, conclusions about the substances within a liquid can be drawn on the analysis of the absorption and the emission spectrum in the case of luminescence effects such as fluorescence.

The invention combines the method of a luminescence measurement and / or a combination of luminescence and absorbance measurement with a device for renal replacement treatment for determining the content of waste products in the dialysate, wherein the determination of the concentration of a particular substance or a combination of substances within the Dialysatabfälle directly from the Composition of the effluent dialysis fluid, which flows out of the dialyzer, depends in a dialysis treatment.

The purpose of this invention is primarily the simple and reliable determination of Dialysatinhaltsstoffen in Dialysatabfluss during a dialysis treatment to ensure the patient adequate treatment success without overloading ("over-dialyze"). At the same time, by evaluating the measurement results, which include either only the results of optical fluorescence measurements or the results of the combination of optical fluorescence and absorbance measurements, it is possible to tailor the treatment of the patient to his specific, individual needs by using dialysis-specific parameters such as Type of dialyzer, type of therapy, level of Dialsatflusses etc. be adapted in the sense of patient success.

Furthermore, the invention serves to realize a device for the accurate determination of waste materials and their amounts in the dialysate outflow during hemodialysis. This invention allows the combination of application of a known technique and the use of a reliable medical device for the determination of proteins / peptides (for example, β ₂ -microglobulin) but also other substances contained in the dialysis fluid after passing through the dialyzer, so that the measurement results influence dialysis parameters such as dialyzer selection, blood flow, dialysate flow, type of therapy and much more.

In a guided by a device according to the invention treatment is now the determination of the content of Dialysierflüssigkeiten in the outflow of dialysis whereby the measurement of the contents and the concentration of the ingredient or a combination of several ingredients in the medium molecular weight range in the dialyzer flowing out dialysis during a dialysis treatment based on a spectral examination by means of luminescence or fluorescence method or by combination of absorbance and luminescence or fluorescence method of dialysis possible to determine dialysis-specific parameters such as blood flow, dialysate flow, ultrafiltration rate, type of therapy, therapy duration.

During therapy, the determination of the ingredient or ingredients within the dialysis fluid in the outflow and / or its concentration in the medium molecular weight range is now possible in real time.

It is also possible during the therapy in real time to determine relative changes of a substance or a substance mixture in the medium molecular range, for example, based on a Kt / V _agent molecules.

The results of the spectral analyzes, together with the specific measurement parameters such as excitation wavelength, emission wavelength, intensity profile of the excitation wavelength, and / or intensity profile of the emission wavelength, can be displayed to deduce the content of a substance or a mixture of substances in the dialysis fluid leaving the dialyzer.

Likewise, the results of the spectral examinations with dialysis parameters such as dialysate flow, blood flow, dialyzer, etc., can be displayed to deduce the content of a substance or a mixture of substances on the blood side of the dialyzer.

In this case, the measurement of the dialysis fluid can be carried out continuously, regularly or sporadically during a dialysis therapy.

Preferably, the spectrophotometric examination is carried out by means of a UV light emitterenden radiation source, since the excitation energies of most of the substances to be determined are in the UV range.

Therefore excitation wavelengths are preferably used for the fluorescence measurement in the range of 1 to 750 nm.

Furthermore, it has proved to be advantageous that now an assessment and Änderbzw. Adjustment of the patient-individual treatment parameters based on the analysis of the measurement results from fluorescence measurement or the combination of fluorescence and absorbance measurement from previous therapies of the same patient and / or the same operators of the device can be made in real time.

The respective removal behavior (relative changes), the reduction rate and / or the dialysis dose Kt / V of one or more uremic substances or of a substance mixture are preferably used as treatment parameters.

The interesting uremic substances are proteins and / or peptides in the mid-molecular range of ~500 to ~50,000 Da, such as β ₂ -microglobulin or the like, as well as small molecular weight substances with a molecular weight of up to ~500 Da such as uric acid, urea or the like.

In a preferred embodiment of the invention, the measurement result or the measurement result in connection with the aforementioned dialysis-specific parameters can be displayed on an output unit such as a screen and / or a printer.

According to a further aspect of the invention, one or more parameters for the dialysis treatment are adaptable in dependence on the measurement result or the measurement result in connection with other dialysis-specific, for example reference data stored in a memory unit, such as eg. B. previous therapies of the same patient and / or the same operator.

It has proved to be particularly advantageous that the adjustment is made automatically.

Alternatively, the adjustment can also be done manually.

It is particularly advantageous if the parameter to be adapted is the blood flow in the extracorporeal bloodstream, the ultrafiltration rate, the dialysate flow, the type of therapy, the dialyzer and / or the dialysis time, since these parameters have a direct influence on the therapy to be carried out.

In order to further automate a possible therapy, the device according to the invention is designed to continuously adjust the adaptation of one or more parameters with which the dialysis therapy is carried out as a function of the measurement result.

Other objects, advantages, features and applications of the present invention will become apparent from the following description of the embodiments with reference to the drawings. All described and / or illustrated features alone or in any meaningful combination form the subject matter of the present invention, also independent of their summary in the claims and their dependency.

Figur 1:

erfindungsgemäße Vorrichtung,

Figur 2:

einen Intensitätsverlauf über die Wellenlänge für die Anregungs- und Emissionswellenlänge von Proteinen/Peptiden oder anderen Substanzen beispielhaft,

Figur 3:

bevorzugter Aufbau einer Sensors zur Fluoreszenzmessung und

Figur 4:

bevorzugter Aufbau einer Kombination aus Fluoreszenz- und Absorbanzmessung.

Show it:

FIG. 1:

device according to the invention,

FIG. 2:

an intensity profile over the wavelength for the excitation and emission wavelength of proteins / peptides or other substances by way of example,

FIG. 3:

preferred construction of a sensor for measuring fluorescence and

FIG. 4:

preferred construction of a combination of fluorescence and absorbance measurement.

FIG. 1 shows the dialysate circuit of a conventional dialysis machine with an additional measuring unit 37, which sits in the dialysate 36. The patient's blood is guided extracorporeally through a tube system 32 into the blood-side chamber 30 of a dialyzer. After the blood has passed the dialyzer, it is returned to the patient via the tube system 31. The blood flow is controlled by the blood pump 33. The dialysis fluid consists of various ingredients which are dissolved in water. Therefore, the dialysis machine has a water inlet 12, two concentrate feeds 16, 18 and two concentrate pumps 17, 19. The water flow 20 together with the concentrate flow determines the composition of the dialysate. Via the water or Dialysatzufluss 20 is the dialysate of the dialysate chamber 29 of the dialyzer, which from the blood chamber 30 through a semi-permeable membrane is separated, supplied. The dialysate is supplied through the dialysate pump 21 to the dialyzer and withdrawn via a further pump 34 together with the ultrafiltrate to the dialyzer. A by-pass connection is mounted between the pumps 21 and 34. Furthermore, the valves 26, 27 and 28 are used to control the Dialysatkreislaufes. Via the tube segment 36, the dialysate after passage through the dialyzer of the measuring unit 37, with which either a pure fluorescence measurement or a combination of fluorescence and absorbance measurement is feasible supplied where the optical measurements take place and then the results via an interface to a associated evaluation device 14 sends. Subsequently, the evaluated data is output via an output unit, such as a screen or printer. After the measurement, the dialysate is fed to a drain 13. The dotted lines 22, 24 and 25 represent optional components of the system for performing a hemodial infiltration. In this case, the substitution fluid comes from a corresponding source 11 and is conveyed via the hose system 22 by means of a pump 23 into the bloodstream of the patient: In the case of Option "post dilution" the Substituat the blood circulation after passing through the dialyzer 24 and in the option "pre dilution" before passing through the dialyzer 25 is supplied. In the case of the "prepost dilution" option, both ports 24 and 25 are used in the delivery of the substituate. The computer 14 controls all elements in FIG. 1 and some others that have been omitted for simplicity. Furthermore, the computer 14 obtains information from the dialysis machine, which can be mathematically linked to the results of the optical measuring device.

FIG. 2 shows a typical course of the intensity as a function of excitation and emission wavelength in a fluorescence measurement. The intensity at low wavelengths thus corresponds to the intensity profile of the excitation wavelength, while the increase in the intensity at longer wavelengths represents the intensity profile of the emission wavelength. The shift in the maximum intensity from excitation to emission wavelength is called stoke shift and is due to non-radiative transitions within the molecule. The solid line describes the spectrums for ambient conditions (pH, T, C, etc.). By changing the Ambient conditions (pH of the dissolved liquid, temperature, etc.) can change both spectra. This is indicated by the dashed line.

FIG. 3 represents the preferred structure of the measuring unit 37 with fluorescence measurement. In principle, however, each sensor unit for a luminescence measurement can be constructed in such a way. Starting from a radiation source 1, electromagnetic radiation 10 (□) of a specific intensity and wavelength profile, for example monochromatic light of wavelength λ = 280 nm, is emitted. This is divided at an optical beam splitter 2. A part of the light is deflected to a reference detector 6 and detected there. The other part of the light, which passes through the beam path divider 2 unhindered, irradiates the sample to be examined in the outlet 3, which represents the used dialysate. Light emitted by luminescence or fluorescence effects leaves the drain located in the outflow 3 and is emitted in all directions. A photodetector 5, which is orthogonal to the original beam path of the radiation source 1, detects the light emitted by the sample. For improved representation of the emitted photons, optical elements 4 such as, for example, optical gratings or other filter devices between drain 3 and photodetector 5 are possible, which are ideally permeable only to the wavelength of interest. By analyzing the wavelength emitted by the test sample, conclusions can be drawn about certain ingredients such as β2-microglobulin2-microglobulin or other proteins / peptides and also their concentration.

FIG. 4 describes the combination of luminescence or fluorescence and absorbance measurement for the determination of dialysatin ingredients in the effluent 3 of the Diaylsierflüssigkeit. The structure is similar to the one in FIG. 3 However, this measuring unit is coupled to an additional absorbance detector 7, which is ideally located in the optical axis of the radiation source 1. The combination of absorbance measurement with simultaneous luminescence or fluorescence measurement enables the measurement of medium molecular weight substances such as β2-microglobulin2-microglobulin while simultaneously checking the purification performance of small molecular weight substances by absorbance measurement.

Again, the preferred wavelength λ = 280nm, but this is variable in a range of 200 to about 400nm. Otherwise, the principle of measurement is strongly related to the principle of measurement in FIG. 3 ajar.

In addition to the preferred embodiment of FIGS. 3 and 4 Further embodiments not explicitly shown here are possible, which also fall within the scope of the claimed invention. For example, the measuring unit 37 can also be designed as a single-beam photometer. This is done on the elements 2 and 6 of the FIGS. 3 and 4 waived. Also, the radiation source 1 can be made in various types. For example, a design as monochromatic or as a polychromatic radiation source is conceivable. In the same way, the optical filter device 4 can be designed both as a bandpass with a single pass range and with a multiple pass range. By varying the radiation source 1 or the filter device 4, molecules of different types can be detected, which allows an assessment of the removal rate of toxic substances from the blood.

In the described embodiment according to the FIGS. 3 and 4 the measurement of the dialysis fluid is carried out continuously over the treatment time. However, it is also possible to perform these measurements at discrete time intervals. The execution of the measurements can be fully automated, but also a manual activation of the measurement is conceivable. The measurement method to be performed is either a pure fluorescence measurement as in Fiugur 2 or a combination of fluorescence and absorbance measurements according to FIG. 3 , The advantage of a combination lies in the fact, the reduction rate of small molecular substances, which with the Absorbanzmessung the EP 1 083 948 B1 can be detected quite well, parallel to the cleaning performance of medium molecular weight substances to determine, and in relation to the cleaning performance medium molecular substances, which can be determined by the fluorescence measurement set. From this combination can draw conclusions not only on the current components of the dialysate, but also on filter properties of the dialyzer, cleaning course of molecules of different molecular size and toxicity and more. to be obtained.

Claims (15)

Device for extracorporeal blood treatment with - A dialyzer, which is divided by a semi-permeable membrane into a first and second chamber (29, 30), wherein the first chamber (29) is arranged in a dialysis fluid and the second chamber (30) by means of a blood supply line (32) and a Blutabführleitung (31) is connectable to the bloodstream of a patient, an inlet (20) for fresh dialysis fluid, a drain (30) for spent dialysis fluid, a measuring device arranged in the outlet, wherein the measuring device has at least one radiation source for substantially monochromatic electromagnetic radiation,
characterized in that
the measuring device (37) for determining a luminescence of the spent dialysis fluid flowing through the outlet (36) has at least one detector system (5) for detecting the intensity of the electromagnetic radiation generated by luminescence. Apparatus according to claim 1, characterized in that the radiation source (1) for emitting electromagnetic radiation in the range of 1 nm to 750 nm, in particular in the range of ultraviolet radiation of 1 nmm to 380 nm is formed. Apparatus according to claim 1 or 2, characterized in that the detector system (5) for detecting electromagnetic radiation in the range of 1 nm to 750 nm is formed. Device according to one of the preceding claims, characterized in that the at least one radiation source (1) for the substantially monochromatic electromagnetic radiation comprises a polychromatic radiation source and a monochromator, in particular an optical filter permeable only to a specific wavelength, or a bandpass filter with one or more has multiple pass ranges. Device according to one of the preceding claims, characterized in that the at least one detector system (5) for detecting the intensity of the electromagnetic radiation generated by luminescence having an only for a specific wavelength transparent optical filter, or a bandpass filter having one or more pass ranges. Device according to one of the preceding claims, characterized in that the detector system (5) is designed as a fluorescence detector. Device according to one of the preceding claims, characterized in that the detector system (5) is arranged with its optical axis substantially orthogonal to the optical axis of the radiation source (1). Device according to one of the preceding claims, characterized in that the measuring device (37) has a reference detector (6). Device according to one of the preceding claims, characterized in that the measuring device (37) has a beam path divider (2) which is arranged between the radiation source (1) and outlet (36). Device according to one of the preceding claims, characterized in that the measuring device (37) has an absorption detector (7) which is preferably arranged in the optical axis of the radiation source (1), wherein between absorption detector (7) and radiation source (1). in the optical axis of the process (36). Device according to one of the preceding claims, characterized in that the radiation source (1) is designed for pulsed or continuous emission of electromagnetic radiation. Device according to one of the preceding claims, characterized in that it comprises a microprocessor unit (14), a memory unit and an output unit (15). Apparatus according to claim 12, characterized in that the memory unit is designed for Speicherrung reference data. Apparatus according to claim 13, characterized in that the microprocessor unit (14) for adapting various device parameters, such. As dialysate flow, blood flow, dialyzer or the like. Based on a comparison of the measured values with the reference data is formed. Device according to one of Claims 12 to 14, characterized in that the measurement results supplied by the detector system (5) can be displayed on the output unit (15), for example a printer or a monitor.

Images